Acetylenically unsaturated diaryl nitriles and derivatives thereof

ABSTRACT

CERTAIN DIARYL-SUBSTITUTED ACETYLENICALLY UNSATURATED COMPOUNS BEARING A CYANO, CARBOXYLIC ACID, ESTER, OR AMIDE SUBSTITUENT OR HYDROXYMETHYL OR AMINOMETHYL, AND OPTIONALLY AN AMINO SUBSTITUENT, EXHIBIT USEFUL CNS ACTIVITY AS ANTICONVULSANTS AND ARE ALSO USEFUL AS ANTIINFLAMMATORY AGENTS AND TRANSQUILIZERS, ETC.

United States Patent (3 M 1m. clfcovc 121/70 US. Cl. 260-465E 4 Claims ABSTRACT OF THE DISCLOSURE Certain diaryl-substituted acetylenically unsaturated compounds bearing a cyano, carboxylic acid, ester, or amide substituent or hydroxymethyl or aminomethyl, and optionally an amino substituent, exhibit useful CNS activity as anticonvulsants and are also useful as antiinflammatory agents and tranquilizers, etc.

This application is a continuation-in-part of our copending application Ser. No. 619,207, filed Feb. 28, 1967, now abandoned.

This invention relates to novel acetylenically unsaturated componds.

The Merck Index (1960) page 380 discloses diphenyl acetic acid and derivatives thereof, namely the methyl and ethyl esters, the amide, nitrile, chloride and anhydride. These compounds do not apparently exhibit any pharmacological activity. The Journal of Medicinal Chemistry 8 (1965) page 313 discloses a compound related to the above-mentioned nitrile, namely 2 benzyl-2-(3- methoxyphenyl)-acetonitrile which also apparently does not exhibit pharmacological activity.

We have now found a new series of compounds, which may be considered as derivatives of the above-mentioned nitriles, and which are interesting chemical intermediates or have surprising pharmacological activity.

The present invention provides acetylenic compounds of the general formula:

OHR1CECR in which rings A and B are substituted or unsubstituted, m is O or 1, X is a cyano radical, an unsubstituted, monosubstituted or disubstituted carb-onarnido radical, a carboxylic acid or salt thereof, a carboxylic acid ester radical, an aminomethyl radical, or a hydroxymethyl radical, R is a hydrogen atom or a methyl radical and R is a hydrogen atom or a primary, secondary or preferably tertiary aminomethyl radical (i.e. -CH N with the -CH group linked to the acetylenically unsaturated carbon atom), provided, that R can be hydrogen only when X is not a cyano-radical.

When the acetylenic'compounds of the above general formula contain a basic nitrogen atom, they can form acid addition salts, and the invention also provides these salts as novel compounds. The acid addition salts may be prepared by reacting the free base with an acid.

The compounds of the above general formula show interesting pharmacological activity and/or are intermediates in the preparation of similar compounds, which 3,594,491 Patented July 20, 1971 show pharmacological activity. They are also useful for testing pharmacological action in laboratory animals.

In general, compounds of the above general formula showed action on the central nervous system when tested in animals, e.g., rats or mice. In general, they exhibit anti-convulsant activity. Additionally, certain of the compounds displayed one or more of the following activities, namely, anti-inflammatory activity, prolongation of barbiturate sleeping time, depressant activity, anorexic activity, analgesic activity, and anti-reserpine activity.

The rings A and B are unsubstituted or are substituted by suitable substituents, for example, alkoxy radicals (preferably methoxy or ethoxy), aralkoxy (e.g., benzyloxy), halogen (e.g., chlorine) or alkyl (e.g., methyl or ethyl). Compounds in which both rings are unsubstituted or in which ring B contains a m-methoxy radical are particularly interesting.

The radical CHR is a branched or straight chained alkylene radical (i.e., R is a methyl radical or a hydrogen atom respectively).

One preferred group of compounds are those in which R is hydrogen, though other interesting compounds are those in which R is a tertiary aminomethyl radical. In these latter compounds, the radical R can be a R2 -OI-I2N/ radical in which R and R each is a lower alkyl (e.g., containing 1 to 4 carbon atoms) or aralkyl radical or together form a heterocyclic ring which may, if desired, contain further hetero atoms and which may be substituted, e.g., by alkyl radicals. Thus, R and R preferably are methyl, ethyl or benzyl or, when R and R form a ring, preferred radicals are pyrrolidino, morpholino, piperidino and 4-methyl and 4-phenyl piperazino radicals.

Preferred starting materials for the preparation of the novel compounds of this invention are compounds having the formula:

H (II) in which A, B, and m have the meanings defined above, and Y is a cyano radical or a carboalkoxy radical, preferably a cyano radical. Such starting materials may be metallated by reaction with a solution or suspension of an alkali metal amide or hydride in an inert solvent, such as liquid ammonium, toluene, benzene, dimethoxy ethane, or dimethyl formamide at temperatures of from 20 C. to C., preferably about room temperature. The metallated derivatives may then be allowed to react with a compound of the general formula Hal-CHR --CECH (III) in which Hal is a halogen atom and R has the meaning defined above. Preferably, Hal is chlorine or bromine; example of suitable halogen compounds for this purpose are propargyl bromide and 3-chloro-but-l-yne.

This reactant of general Formula III may be added after cooling the solution of the metallated derivative of a compound of general Formula II to between 20 and +20 C. This reaction can be elfected very conveniently at room temperature though other suitable temperatures can be used, e.g., to 40 C. Subsequent addition of water enables the alkali metal halide formed to be separated from the organic solution which may then be worked up in known manner. From such a reaction there may be obtained intermediates of formula CHR1CECH (IV) which may be readily converted to the novel compounds of this invention by the methods described and exemplified below. (The compounds of Formula IV may be contaminated with the corresponding allene and so further purification may sometimes be necessary or desirable.)

Compounds of general Formula I in which R is hydrogen and X is other than cyano or ester groupings can be obtained by subsequent treatment of the nitrile or ester, as will be described below.

To prepare the compound of general Formula I containing an aminomethyl radical as substituent R, a Mannich reaction is carried out on the compound of general Formula I in which R is a hydrogen atom under the usual conditions for a Mannich reaction. For this purpose, the compound of general Formula I in which R is hydrogen can be reacted with formaldehyde (e.g., as paraformaldehyde) and the appropriate secondary amine of the general formula (in which R and R have the meanings defined above). The solution preferably contains mercuric acetate or cuprous chloride. A particularly suitable inert solvent for the reaction is dioxane. Heating at temperatures of 30 to 120 C., e.g., on a steam bath is very convenient. The desired product may be worked up in known manner. However, the compound which undergoes the Mannich reaction advantageously should contain a free active hydrogen atom only as the substituent R on the acetylenic carbon atom. Accordingly, if the desired final product is to contain other reactive hydrogen atoms, these advisably should either be blocked on the reactant before the Mannich reaction is carried out, or formed in the appropriate position on the product of the Mannich reaction. Thus, when a compound is to be prepared in which X is other than a cyano or ester group, it is usually necessary to prepare the corresponding nitrile or ester of general Formula I and only then to convert the cyano or ester grouping to the desired group, as is more fully described below. If a nitrile (i.e., X is a CN radical) is obtained by the above sequence of reactions, it can be converted to the corresponding primary amide (i.e., X is CONH for example by hydrolysis with hydrogen peroxide containing a caustic alkali, for example sodium hydroxide. The acid (i.e., X is CO H) can be obtained by hydrolysis of the primary amide or ester, in acid solution. The acid can be converted to the secondary or tertiary amide by reaction with the appropriate amine, e.g., with an alkylamine. Alternatively, if desired the nitrile can be reduced with a reducing agent which will not attack a triple bond, for example with lithium aluminum hydride, to the amine (X then becomes a CH NH radical).

If an ester is obtained by the above sequence of reaction it can, if desired, be saponified to the acid or reacted with an amine to give the amide. Futhermore, the ester may be reduced, if desired, to the primary alcohol.

The initial unsubstituted starting materials of general Formula II, in which X is cyano can be prepared as follows:

When In is 0 in the compounds of general Formula II, a Friedel-Crafts reaction can be effected between benzene and ot-bromobenzyl nitrile. When m is 1 in the compound of general Formula II benzyl nitrile can be condensed with benzaldehyde and the product reduced. When a substituted starting material is required, the benzene rings can be substituted at the appropriate positions by radicals which are inert in the above reaciton. The other starting materials of this type can be made in similar manner or can be derived from the nitriles.

As stated above, the compounds of the invention genrally have interesting pharmacological properties, and the present invention also provides pharmaceutical compositions comprising compounds of general Formula I, or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof (when the compound contains a basic nitrogen atom), and a pharmaceutical carrier. There may be administered orally or parenterally.

The pharmaceutically acceptable carrier used in the composition of the invention can be solid or liquid. Solid compositions include powders, tablets, dispersible granules, capsules, cachets and suppositories. A solid carrier can be one or more substances which may also act as fiavouring agents, binders or tablets distintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely-divided solid which is in admixture with the finelydivided active compound. In tablets the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the size and shape desired. The powders and tablets preferably contain 5 to 10 to 99% of the active compound. Suitable solid carriers are, for example, magnesium carbonate or stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, a low melting wax and cocoa butter. The term composition is intended to include the formulation of the active compound with encapsulating material as carrier to give a capsule in which the active compound with or without carriers) is thus in association with it. Similarly, cachets are included.

Liquid form compositions include solutions, suspensions or emulsions. The active compound may be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as sterile water preferably containing a non-ionic surface active agent such as the esters, e.g., fatty acid esters of polyhydroxy compounds, e.g., sorbitan, and particularly their polyethylene oxide derivatives for instance Tween 80. (Tween is a registered trademark.) It may be dissolved in an organic solvent or a mixture thereof and it may contain fiavouring agents or other substances.

Conveniently the composition is in a sterile form suitable for parenteral injection. The active compound can be dispersed, e.g., dissolved in a suitable organic solvent, for instance aqueous propyleneglycol or polyethylene glycol. In other instances compositions can be made by dispersing the finely-divided active compound in aqueous starch in sodium carboxymethyl cellulose solution: or in a suitable oil, for instance arachis oil. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by intramuscular, intraperitoneal, subcutaneous or intravenous in- JCCtlOIl.

In unit dose form the composition can be a packaged composition, the package containing discrete quantities of composition, for example, packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be the appropriate number of any of these in packaged form.

To prepare a composition in unit dosage form in accordance with the invention, the active compound can be mixed with a carrier and divided into unit dosage form. However, if desired the active compound can be used in the absence of a carrier.

The following examples illustrate the invention.

EXAMPLE 1 l-cyano-l,1-diphenyl-3-butyne (a) Diphenyl acetonitrile (193 g. 1.0 mole) in dry toluene (400 ml.) was added dropwise with stirring to a suspension of sodamide (39.2 g. 1.0 mole) in toluene (100 ml.). After a small quantity of the diphenyl acetonitrile had been added the reaction mixture was gently warmed to initiate the mildly exothermic reaction evolving ammonia. The reaction temperature was controlled by adjusting the rate of addition of the diphenyl acetonitrile.

'(b) When the addition had been completed the reaction mixture was heated under reflux for 1 hour, cooled to 10 C. and 3-bromo-1-propyne (130 g. 1.1 mole) in toluene (5O mls.) Was added. The reaction mixture was maintained at between and C. by external cooling. On completion of the addition the reaction mixture was left for several hours at room temperature. Water (100 ml.) was cautiously added. The organic phase was separated and washed with 2 N HCl. After drying the organic phase over anhydrous magnesium sulphate, the solvent was removed under reduced pressure to leave a red oil which crystallized from 90% ethanol as yellow rhombs of melting point 61 C. Recrystallization from 95% methanol (after purification using charcoal) yielded 160 g. (70%) of colorless needles, M.P. 63-64 C.

EXAMPLE 2 l-cyano-1,1-diphenyl-2-methyl-3-butyne (a) 1,1-diphenyl acetonitrile (51.5 g. 0.26 mole) in toluene (100 ml.') was added with stirring to a suspension of sodamide (11.7 g. 0.3 mole) in toluene ml). On warming, a red suspension of the sodium salt of the nitrile was formed.

(b) The reaction mixture was heated under reflux for 1 hour, then cooled to 10 C. 3-chloro-1-butyne (28.0 g. 0.31 mole) was added dropwise when an exothermic reaction took place; the reaction temperature was maintained between 10-15" C. by external cooling. On completion of the addition, the reaction mixture was left overnight, at room temperature, then washed with water to give a red oil which was distilled at 176-200 C. and 0.2 mm. when 52.0 g. (80%) of the desired compound were obtained. This was crystallized from absolute ethanol to give white rhombs (24.3 g. 37%).

Analysis.Found (percent): C, 88.2; H, 6.2; N, 5.9. C H N requires (percent): C, 88.1; H, 6.2; N, 5.7.

EXAMPLE 3 l-benzyl-l-cyano-l-phenyl-3-butyne (a) l-phenyl-l-benzyl-acetonitrile (20.7, 0.1 m.) in dry toluene (40 ml.) was reacted with sodamide (4.2 g. 0.11 m.) in dry toluene (10 ml.) in the manner described in Example 1.

(b) 3-bromo-1-propyne (11.8 g. 0.1 mole) in toluene (550 mls.) was reacted with the product in the manner described in Example 1. After working up as described in that example, l-benzyl-l-cyano-1-phenyl-3-butyne was obtained as colorless rhombs of melting point 75-6 C. after recrystallization from aqueous methanol. Yield 14.5 g. (60%).

Analysis.-Found (percent): C, 88.0; H, 6.0; N, 5.7. C H N requires (percent): C, 88.2; H, 6.2; N, 5.7.

EXAMPLE 4 l-benzyl- 1 -cyano- 1- (.m-methoxyphenyl -2-butyne (a) 1 benzyl 1 (m methoxyphenyl)acetonitrile (23.7 g. 0.1 mole) in dry toluene (50 ml.) was reacted With sodamide (4.2 g. 0.11 mole) in toluene (10 ml.) in the manner described in Example 1.

(b) 3-bromo-1-propyne (13.0 g.'0.11 mole) in toluene (50 mls.) was reacted with the product in the manner described in Example 1. After working up as described in that example, l-benzyl-l-cyano-l-(m-methoxyphenyl)-3- butyne was obtained as colorless rhombs of melting point 92-3 C. after recrystallization from aqueous methanol. Yield 11.0 g.

Analysis.Found (percent): C, 83.0; H, 6.3; N, 5.3; C19H17NO requires (percent): C, 82.9; H, 6.4; N, 5.1.

EXAMPLE 5 Ethyl-2,2-diphenyl-4-pentynoate (a) Ethyl 1,1-diphenyl acetate (0.15 mole 36 g.) in dry dimethyl formamide (75 mls.) was added to a stirred suspension of sodium hydride (0.15 mole 7.2 g. of 50% dispersion in oil) in dimethyl formamide (50 ml.). An exothermic reaction occurred and the reaction mixture which became yellow in color was maintained between 2025 C. by external cooling.

(b) On completion of the addition, the reaction mixture was stirred for a further 3 hours at room temperature, cooled to 15 C. and 3-bromo-1-propyne (19.1 g. 0.16 mole) added dropwise keeping the temperature between 2030 C. by external cooling. The reaction mixture was left overnight at room temperature and had a pH of 7. The sodium bromide was filtered off and the dimethyl formamide was removed under reduced .pressure to leave an oil which was taken up in benzene and Washed with water. After drying once over anhydrous magnesium sulphate, the product was distilled to yield the ester, B.P. -141 C. at 0.5 mm. Yield 19.4 g. (50%) of a colorless oil of [M 1.5642.

Analysis.Found (percent): C, 81.8; H, 6.4; C H O requires (percent): C, 82.0; H, 6.5.

EXAMPLE 6 2,2-diphenyl-4-pentynoic acid Ethyl 2,2-diphenyl-4-pentynoate (4.17 g.) was heated under reflux with potassium hydroxide (2.8 g.) in 50% ethanol (40 ml.) until the oil had gone into solution. The ethanol was removed under reduced pressure and the residual oil extracted with ether. The aqueous, basic, solution was acidified with concentrated hydrochloric acid and re-extracted with ether. After drying, the ether was removed to leave a White solid which after recrystallization from benzene/petrol afforded 2.15 g. of line white needles, M.P. 181182 C.

Analysis.-Found (percent): C, 80.7; H, 5.7; C H O requires (percent): C, 81.6; H, 5.6.

EXAMPLE 7 1,1-dipheny1-3-butyne-l-carboxamide The product of Example 1 (23 g. 0.1 mole) in ethanol (600 ml.) was added to a stirred solution of 30% hydrogen peroxide (180 mls.) and -N-sodium hydroxide (600 mls.). The mixture was stirred at room temperature for 1 68 hours, left at 0 C. for 24 hours and the white amorphous material filtered off to yield 21 g. (89%) M.P. -167 C. Recrystallization from benzene/petroleum ether afforded colorless rhombs M.P. 163164 C.

Analysis.Found (percent): C, 81.5; H, 5.8; N, 5.6; C17H15N0 requires (percent): C, 81.9; H, 6.0; N, 5.6.

This compound exhibits activity against metrazol seizures and showed anticonvulsant activity in an amount of about of its LD i.p. in mice which was 561 mg./kg.

EXAMPLE 8 1,1-dipheny1-2-methyl-3-hutyne-l-carboxamide 1 cyano 1,1 diphenyl-2-methyl-3 butyne (5.83 g. 0.023 mole) in ethanol (200 ml.) was stirred for 168 hoursat room temperature with a mixture of hydrogen peroxide (30% 43 mls.) and N-sodium hydroxide (138 mls.). At the end of this time the solid material remaining was removed by filtration and 3.44 g. of starting material obtained. Evaporation of the mother liquors afforded 1.0 g. i.e., 16% of the carboxamide as colorless rhombs, M.P. 150-15 1 C. Recrystallization from benzene and petrol (B.P. 80100 C.) raised the M.P. to 1512 C.

Analysis.Found (percent): C, 82.3; H, 6.7; N, 5.5; C H NO requires (percent): C, 82.1; H, 6.5; N, 5.3.

EXAMPLE 9 l-amino-2,2-diphenyl-4-pentyne l-cyano-l,1-diphenyl-3-butyne (9.2 g. 0.04 mole) in dry diethyl ether (120 ml.) was added dropwise to a stirred suspension of lithium aluminum hydride (2.4 g. 0.06 mole) in diethyl ether (200 ml.) at such a rate that gentle refluxing occurred. On completion of the addition the stirred mixture, from which a White complex had separated, was heated under reflux for a further 2 hours.

The mixture was cooled and the complex decomposed by the cautious addition of water rnls.), the suspension was stirred for minutes then filtered. The filtrate was evaporated to dryness to leave a colorless oil which deposited microneedles on treatment in isopropanol with a solution of hydrogen chloride in dry ether; 7.4 g. (68%), M.P. 199202 C. Recrystallization from isopropanol afforded colorless needles, M.P. 204-6 C. (d.).

AnaIysis.-Found (percent): C, 74.7; H, 6.8; N, 5.4; Cl, 13.25; C H ClN requires (percent): C, 75.1; H, 6.7; N, 5.15; Cl, 13.1.

This compound exhibited anti-reserpine properties in both ptosis and hypothermia tests. It also showed anorexic activity, analgesic activity, potentiated the action of barbiturates, and depressed polysynaptic reflexes in a cat. The LD i.p. in mice was 105 trig/kg.

EXAMPLE 10 l-benzyl-l- (m-methoxyphenyl -3-butyne-1-carboxamide 1 benzyl-l-(m-methoxyphenyl)-1-cyano-3-butyne (5.5 g., 0.2 mole) in ethanol (150 ml.) was reacted with 30% hydrogen peroxide ml., 0.3 m.) and 2 N-sodium hydroxide (60 ml., 0.12 m.) by the procedure of Example 7.

After recrystallization from petrol (B.P. 100 C.) benzene/ether mixture (1: 1:1 by volume), l-benzyl-l- (m-methoxyphenyl)-(3-butyne)-1-carboxamide (6.4 g. 78.5%) of melting point 106-110 C. was obtained.

EXAMPLE 11 l-benzyl-1-phenyl-3-butyne-l-carboxamide l-benzyl-l-phenyl-1-cyano-3-'butyne (4.9 g.) in ethanol ml.) was reacted with a stirred solution of 30% hydrogen peroxide (35 ml.) and 2 N-sodium hydroxide ml.) by the procedure of Example 7 to give l-benzyl- 1-phenyl-3-butyne-l-carboxamide having melting point 1478 C.

Administered orally, this compound protects mice against metrazol-induced convulsions. The ED is 80 mg./kg., and the LD is 290 mg./kg.

EXAMPLE 12 2,2-diphenyl-4-pentyne-l-ol Ethyl 2,2-diphenyl-4-pentynoate (7.75 g., 0.03 mole) in dry diethyl ether (50 ml.) was added dropwise to a stirred suspension of lithium aluminum hydride (1.14 g., 0.03 mole) in dry ether (50 ml.). On completion of the addition the reaction mixture was heated under reflux for 2 /2 hours, then cooled and decomposed by the dropwise addition of water ((5 ml.). The mixture was stirred, refluxed for 30 minutes then filtered, and the ether removed and the product distilled to yield a cloudy viscous oil, B.P. 122-130 C. at 0.05 mm. (5.0 g., 70%).

Analysis.Found (percent): C, 84.8; H, 6.9; active hydrogen 0.8. C H O requires (percent): C, 86.4; H, 6.8; active hydrogen 0.75.

Administered intraperitoneally, this compound protects against metrazol-induced convulsions in mice. The ED is 127 mg./kg., and the LD is in excess of 1000 mg./kg.

8 EXAMPLE 13 2-benzyl-2-phenyl-4-pentynamine 2-benzyl-2-phenyl-4-pentynenitrile (12.25 g.) in dry ether (100 ml.) was added dropwise to a stirred suspension of aluminum lithium hydride (3.8 g.) in ether (100 ml.). On completion of addition the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was decomposed by the addition of water, magnesium sulphate was added and the mixture filtered. The ether was removed under reduced pressure to leave a colorless oil. The oil was dissolved in propan-Z-ol and a solution of hydrogen chloride in dry ether added. The title compound was obtained as a monohydrate (5.6 g.), M.P. 164- C.

Analysis.Found (percent): C, 71.4; H, 7.4; N, 4.4; Cl, 11.55. C H N.H O-HCl requires (percent): C, 71.1; H, 7.3; N, 4.6; Cl, 11.7.

This compound protects against metrazol-induced con vulsions in mice.

EXAMPLE 14 2-benzyl-2- (m-methoxyphenyl) -4-pentynenitrile Z-(m-methoxyphenyl)-3-phenyl-propionitrile (23.7 g.) in dry toluene (50 ml.) was added dropwise to a suspension of sodium amide (4.2 g.) in toluene (200 ml.). On completion of the addition the mixture was heated under reflux for 2 hours. The reaction mixture was cooled and 3-bromo-1-propyne (9 ml.) was added dropwise keeping the temperature of the reaction below 10 C. The reaction mixture was left overnight and then poured into water. After drying, the organic phase on evaporation afforded crystals from ethanol, 11.0 g., M.P. 92-3 C.

Analysis.Found (percent): C, 83.0; H, 6.3; N, 5.3. C19H1I7NO requires (percent): C, 82.9; H, 6.4; N, 5.1.

EXAMPLE 15 2- (o-chlorophenyl) -2-phenyl-4-pentynenitrile 2-(o-chlorophenyl)-phenylacetonitrile (5.0 g.) in dry dimethyl formamide (5 ml.) was added to a suspension of sodium hydride (1.0 g., 50% in oil) in dry dimethyl formamide (10 ml.). After stirring at room temperature for 1 hour the reaction mixture was cooled to 10 C. and 3-bromo-1-propyne (2.9 g.) added dropwise. The reaction mixture was stirred for 2 hours, poured into water and extracted with benzene. The benzene extracts were washed with water, dried and evaporated to an oil which gave 3.4 g. of white chunky crystals, M.P. 99-100 C. from methanol.

Analysis-Found (percent): C, 77.3; H, 4.6; N, 5.3; Cl, 13.0. CnHmNC]. requires (percent): C, 76.8; H, 4.55; N, 5.3; CI, 13.3.

This compound is an anticonvulsant.

EXAMPLE 16 2,2-diphenyl-4-pentynoic-acid dimethylaminoethylester Ethyl 2,2-diphenyl-4-pentynoate (13.9 g.) and dimethyl aminoethanol (50 ml.) were dissolved in dry benzene (100 ml.) and heated to reflux temperature. A small pea of sodium was added and the benzene/ethanol azeotrope removed through a fractionating column filled with singleturn glass helices. When the theoretical amount of azeotrope had separated, the benzene and excess dimethylamine and ethanol were removed under reduced pressure and the residue dissolved in 2 N hydrochloric acid and extracted with ether. The aqueous layer was basified and extracted with ether. After drying, the ether was removed to leave a viscous oil. Distillation afforded 9.8 g. of a colorless viscous oil, B.P./0.07 mm. 148 C.

Aanlysis.Found (percent): C, 78.4; H, 7.2; N, 4.4. C H NO requires (percent): C, 78.5; H, 7.2; N, 4.4.

This compound has anticonvulsant activity.

9 EXAMPLE 17 S-cyano-S ,5 -diphenyl-l-piperidino-Lpentyne l-cyano-l,l-diphenyl-3-butyne (22 g., 0.1 mole) in dioxane (100 ml.) was heated on a steam bath for 2 hours with paraformaldehyde (3.6 g. 0.04 mole), piperidine (8.8 g., 0.12 mole) and cuprous chloride (120 mg). The dioxane was removed by distillation and the residue dissolved in ether and extracted with 2 N hydrochloric acid.

The aqueous layer was basified, extracted with ether, dried over anhydrous magnesium sulphate and evaporated to yield the desired Mannich base as an oil. On treatment with hydrogen chloride in ether the hydrochloride was obtained as a crystalline solid. After recrystallization from isopropyl alcohol/ether, 23.1 grams 66% were obtained of melting point 215216 C.

Analysis.-Found (percent): C, 76.2; H, 7.0; N, 7.6; C1, 9.3. C H N C1 requires (percent): C, 76.5; H, 7.0; N, 7.6; Cl, 9.8.

This compound gave protection against metrazol-induced convulsions in mice at approximately its LD when given interperitoneally. The LD i.p. in mice was 270 rng./kg.

EXAMPLE 18 S-cyano-S ,5 -diphenyll-diethylamino-Z-pentyne l-cyano 1,1 diphenyl 3 butyne (11.0 g. 0.05 mole) in dioxane (50 ml.) was reacted with paraformaldehyde (1.8 g. 0.22 mole) and diethylamine (4.4 g. 0.06 mole) by heating on a steam bath for 2 hours in the presence of a catalytic quantity of cuprous chloride.

The desired Mannich base (13.88 g. 85%) was isolated from the reaction mixture by the usual method in the form of its crystalline hydrochloride. After crystallization from isopropyl alcohol/ether, 12.6 grams Were obtained having melting point 193 C.

Analysis.--Found (percent): C, 75.1; H, 7.2; N, 8.0; CI, 9.7. C H N Cl requires (percent): C, 74.9; H, 7.1; N, 7.7; Cl, 10.05.

The compound gave significant protection against metrazol-induced and maximal electroshock induced convulsions in mice and showed analgesic activity at A of its LD The LD i.p. in mice was 168 mg./kg.

EXAMPLE 19 5 -cyano-5 ,5 -diphenyl-l-benzylmethylamino- 2-pentyne 1-cyano-1,1-diphenyl-3-butyne (11.0 g.) in dioxane (50 mls.) was reacted with paraformaldehyde (1.8 g.) and benzylmethylamine (9.2 g. 0.3 mole) in the manner described in Example 17.

The desired Mannich base (11 g. 55%) was obtained in the form of its crystalline hydrochloride.

After recrystallization from isopropyl alcohol/ether 10.62 grams were obtained having a melting point 221 C.

Analysis.Found (percent): C, 77.3; H, 6.5; N, 6.8; Cl, 9.4. C H N Cl requires (percent): C, 77.8; H, 6.3; N, 7.0; Cl, 8.8.

This compound more than doubled the barbiturate sleeping time of mice when administered interperitoneally at 40 mg./kg. The LD i.p. in mice was more than 1000 mg./kg. The compound also protected against metrazolinduced convulsions in mice.

EXAMPLE 20 5 -cyano-5 ,5 -diphenyl- I-morpholino- 2-pentyne 1 cyano 1,1 diphenyl 3 butyne (11.0 g.) in dioxane (100 mls.) was reacted in the manner described in Example 16 with paraformaldehyde 1.8 g.), morpholine (6.0 g.) and cuprous chloride (100 mg.) and worked up in the manner described in that example. The desired Mannich base was obtained in the form of its crystalline hydrochloride.

After recrystallization from isopropyl alcohol/ether, 8.5 g. of S-cyano 5,5 diphenyl 1 morpholino-2- pentyne, monohydrochloride were obtained having melting point 221 C.

Analysis.Found (percent): C, 71.8; H, 6.0; N, 7.3; Cl, 9.25. CgzHggNzO'HCl requires (percent): C, 72.0; H, 6.3; N, 7.6; Cl, 9.7.

The LD i.p. in mice was 630 mg./kg. The compound protects mice against metrazol-induced convulsions, exhibiting an ED of 260 mg./ kg. when administered intraperitoneally.

EXAMPLE 21 5 -cyano-5 ,5 -diphenyl-l-pyrrolidino-Z-pentyne l-cyano 1,1 diphenyl -3 butyne (9.3 g.) in dioxane ml.) was reacted in the manner described in Example 17 with paraformaldehyde (1.38 g.), pyrrolidine (3.1 g.), and cuprous chloride (100 mg.) and worked up in the manner described in that example.

The desired Mannich base was obtained in the form of its crystalline hydrochloride. Yield 43%, MP. 204 5 C.

Analysis.Found (percent): C, 75.4; H, 6.2; N, 8.0; Cl, 11.35. C H N Hcl requires (percent): C, 75.5; H, 6.3; N, 8.0; Cl, 11.4.

This compound showed anticonvulsant activity and depressant activity when administered interperitoneally at A1 of its LD It doubled the hexabarbital sleeping time in mice at a dose of 60 mg./kg. The LD in mice was 137 mg./kg.

EXAMPLE 22 5-cyano-5,5-diphenyl1-(4-methy1-piperazino)- 2-pentyne l-cyano 1,1 diphenyl 3 butyne (11 g. 0.05 mole) in dioxane (50 ml.) was reacted with paraformaldehyde (1.8 g. 0.02 mole) and N-methyl-piperazine (6.0 g. 0.06 mole) in the manner described in Example 17. The desired Mannich base in the form of its dihydrochloride (14.3 g. 75%) was obtained as a crystalline solid, M.P. 230232 C.

Analysis.Found (percent): C, 66.1; H, 6.9; N, 9.9; Cl, 16.9. C H N Cl requires (percent): C, 66.3; H, 6.5; N, 10.1; C1, 17.0.

This compound showed anticonvulsant activity in giving protection against metrazol-induced convulsions (ED =80 rug/kg.) and maximal electroshock seizures. The LD i.p. in mice was 227 mg./kg.

EXAMPLE 23 1-piperidino-S-cyano-S-benzyl-6- (rn-methoxyphenyl)-2-pentyne l-benzyl 1 cyano 1 (m-methoxyphenyl)-3-butyne (6.6 grams, 0.025 mole) in dioxane (50 mls.) was heated on a steam bath with paraformaldehyde (1.2 g.) piperidine (3.0 g.) and cuprous chloride, (40 mg.). The dioxane was removed by distillation and the residue dissolved in ether and extracted with 2 N-hydrochloric acid. The aqueous layer was basified, extracted with ether, the ether extracts dried over magnesium sulphate and evaporated to yield the desired Mannich base (6.0 g. 66%) in the form of its crystalline hydrochloride, M.P. C.

Analysis.-Found (percent): C, 73.3; H, 7.2; N, 6.9; Cl, 8.5. C H N OCl requires (percent): C, 73.4; H, 7.15; N, 6.85; Cl, 8.7.

The LD i.p. in mice was 250 mg./kg. The compound protects against metrazol-induced convulsions in mice.

EXAMPLE 24 l-diethylamino-4-methyl-5 -cyano-5 ,5 -diphenyl-2-pentyne l-cyano 2 methyl-1,1-diphenyl-3-butyne (6.3 g. 0.025 mole) in dioxane (50 mls.) was heated on a steam bath with paraformaldehyde (1.1 g.), diethylamine (2.2 g. 0.03

mole) and cuprous chloride (70 mg.) for 6 hours. The dioxane was removed by distillation and the residue was dissolved in ether and extracted with 2 N-hydrochloric acid. The aqueous extracts were basified, extracted with ether, dried over magnesium sulphate and evaporated to yield the desired Mannich base isolated in the form of its hydrochloride 5.05 g. (61% M.P. 169-170" C.

Analysis.-Found (percent): C, 75.0; H, 7.6; N, 7.5; Cl, 9.5. C H N HCI requires (percent): C, 75.3; H, 7.4; N, 7.6; Cl, 7.9.

The compound protects against metrazol-induced convulsions in mice; ED (intraperitoneally)=60 mg./kg. LD =445.

EXAMPLE 25 5-benzyl-5-cyano-5-(m-rnethoxyphenyl)-1-(4-methylpiperazino -2-pentyne l-cyano 1 benzyl 1 (m-methoxyphenyl)-3-'butyne (5.5 g.) in dioxane (50 mls.) was heated on a steam bath with paraformaldehyde (0.72 g. 0.02 mole), N-methylpiperazine (3 g. 0.03 mole) and cuprous chloride (60 mg.). The dioxane was removed by distillation and the residue dissolved in ether and extracted with dilute hydrochloric acid. The aqueous layer was basified, extracted with ether, the extracts dried over magnesium sulphate and evaporated to yield the desired Mannich base (6.4 g. 74.3%) isolated in the form of its crystalline dihydrochloride, M.P. 202-208 C. (decomp.).

Analysis.--Found (percent) C, 65.1; H, 7.0; N, 8.95; Cl, 15.3. C H Cl N O requires (percent): C, 65.2; H, 6.8; N, 9.1; CI, 15.4.

The compound protects against metrazol-induced convulsions in mice. ED =40 mg./kg. (p.o.), LD :177 mg./kg.

EXAMPLE 26 5 -cyano-5 -benzyl-5 -phenyl- 1 4-methyl pi perazino) 2-pentyne l-cyano 1 benzyl 1 phenyl-3-butyne (4.9 g. 0.02 mole) in dioxane (50 mls.) was heated on a steam bath with paraformaldehyde (0.72 g. 0.02 mole), N-methylpiperazine (3 g. 0.03 mole) and cuprous chloride (60 mg.). The dioxane was removed by distillation and the residue dissolved in ether and extracted with dilute hydrochloric acid. The aqueous layer was basified, extracted with ether, the extracts dried over magnesium sulphate and evaporated to yield the desired Mannich base (4.7 g. 54.5%) isolated in the form of its crystalline dihydrochloride, M.P. 208212 C. (decomp.).

Analysis.- Found (percent): C, 64.8; H, 7.1; N, 9.2; Cl, 15.8 C H N -2HCl-H O requires (percent): C, 64.3; H, 7.0; N, 9.4; Cl, 15.8.

This compound protects against metrazol-induced convulsions in mice. The ED (intraperitoneally) is 84 mg./ kg., and the LD is 198 mg./kg.

EXAMPLE 27 S-cyano-S,5-diphenyl-4-methyl-1-morpholino-2-pentyne l-cyano 2 methyl 1,1 diphenyl-3-butyne (10.3 g. 0.042 mole) was heated in a steam bath for 4 hours with paraformaldehyde (1.35 g. 0.045 mole), morpholine (4.1 g. 0.047 mole) and cuprous chloride (100 mg.). The reaction was worked up as described in Example 17 to yield the Mannich base as the hydrochloride. Yield 8.7 g., M.P. l946 C. Recrystallization from isopropyl alcohol/diethyl ether afforded 7.41 g. (46% M.P. 198-200 C.

Analysis.Found (percent) C, 72.3; H, 6.6; Cl, 9.3; N, 7.3. C H N O-HCl requires (percent): C, 72.5; H, 6.6; Cl, 9.3; N, 7.35.

This compound protects (ED p.o.=400 mg./kg.) against metrazol-induced convulsions in mice. LD 1000 mg./kg. 1

1 2 EXAMPLE 2s 4-methyl-5 -cyano-5 ,5 -diphenyll-piperidino-Z-pentyne l-cyano-Z-methyl 1,1 diphenyl 3 butyne (5.34 g.) was heated on a steam bath with paraformaldehyde (0.9 g.), piperidine (2.1 g.) and cuprous chloride (70 mg.) in dioxane (25 mls.) for 4 hours working up as described in Example 17. Yield 3.6 g. of the hydrochloride monohydrate. Recrystallization from isopropyl alcohol gave 3.2 g. of colorless needles, M.P. 220-223 C.

Analysis.-Found (percent) C, 74.2; H, 7.1; N, 7.1; Cl, 9.0. C H N HCl-H O requires (percent): C, 74.1; H, 7.4; N, 7.2; CI, 9.1.

The compound protects against metrazol-induced convulsions in mice.

EXAMPLE 29 Ethyl-2,2-diphenyl-6-piperidino-4-hexynoate Ethyl-2,2-diphenyl-4-pentynoate (13.9 g. 0.05 mole) was heated on a steam bath for 6 hours, with piperidine (8.25 mls. 0.06 mole), paraformaldehyde (1.8 g. 0.1 mole) and cuprous chloride (50 mg.) in dioxane mls.). The dioxane was removed under reduced pressure to leave a brown viscous oil which was dissolved in dilute hydrochloric acid and extracted with ether. The aqueous layer was basified and extracted with ether. The ether extracts were dried over anhydrous magnesium sulphate the ether removed under reduced pressure and the oil distilled, B.P. 170-176 C. at 0.05 mm. (7.72 g.) [11] 1.5589.

Analysis.Found (percent): C, 79.9; H, 7.7; N, 3.9. C H NO requires (percent): C, 78.0; H, 7.8; N, 3.7.

The compound, administered intraperitoneally, protects against metrazol-induced convulsions in mice. ED =40, LD =574.

EXAMPLE 30 2,2-diphenyl-6-(4-phenyl-piperazinyl -4-hexynenitrile 2,2-diphenyl-4-pentynenitrile (11 g.), paraformaldehyde (1.8 g.), l-phenylpiperazine (9.72 g.), cuprous chloride (120 mg.) and dioxane (100 mls.) was heated on a steam bath for 1.5 hours. The dioxane was removed under reduced pressure leaving an oil which was dissolved in 2 N hydrochloric aicd and extracted with ether. The yellow solid obtained was filtered, in hot propane-Z-ol and the solution acidified with concentrated hydrochloric acid. 103 g. of the hydrochloride were obtained, M.P. 214- 216 C.

Analysis.-Found (percent): C, 76.2; H, 6.3; N, 9.4; Cl, 7.9. C H N -HCl requires (percent): C, 76.0; H, 6.4; N, 9.5; Cl, 8.0.

This compound is a very effective anticonvulsont, as shown by it having a median effective dose against metrazol-induced convulsions of 40 mg./kg., whereas is median lethal dose is in excess of 1000 mg./kg.

EXAMPLE 31 6- benzylmethylamino -2,2-diphenyl-4-hexynamide 6 (benzylmethylamino)-2,2-diphenyl-4-pentynenitrile (10 g.) was stirred at room temperature with 30% hydrogen peroxide (45' mls.) and N sodium hydroxide (250 mls.) in ethanol (200 mls.). The ethanol was removed under reduced pressure and the residual oil extracted into benzene. After drying, the benzene was removed under reduced pressure to leave an oil which was crystallized from propan-2-ol affording 5.3 g. of colorless crystals, M.P. 1056 C.

Analysis.Found (percent): C, 81.7; H, 6.7; N, 7.4. C H N O requires (percent): C, 82.0; H, 6.7; N, 7.45.

This compound shows anticonvulsant activity when tested in mice against metrazol-induced convulsions.

Ethyl 2,2-diphenyl-4-pentynoate (41 -g.), diethylamine (9.15 g.) and paraforrnaldehyde (3.7 g.) was heated on a steam bath in dioxane (100 ml.) containing cuprous bromide 120 mg), for 2 hours. The dioxane was removed under reduced presure and the oil dissolved in 2 N hydrochloric acid. After the acid layer had been extracted with ether it was basified with 2 N sodium hydroxide. The oil was extracted with ether, dried, and after drying evaporated to yield an oil which was distilled affording 30.1 g. of oil, B.P./ 0.3 mm. 18590 C.

Analysis.--Found (percent): 79.0; H, 7.85; N, 4.0. C H NO requires (percent): C, 79.3; H, 8.0; N, 3.85.

This compound protects mice against metrazol-induced convulsions, showing an ED (i.p.) of 40 mg./kg. and an LD of 314 mg./kg.

EXAMPLE 3 3 6-diethylamino-2,2-diphenyl-4-hexyne-1-01 Ethyl 6 diethylamino-Z,2-diphenyl-4-hexynoate (4.7 g.)- in dry ether (50 ml.) was added dropwise to a stirred suspension of aluminum lithium hydride (0.52 g.) in dry ether (50 mls.). The reaction was heated under reflux for 2 hours. After cooling, the complex was decomposed by the addition of water (5 mls.). Anhydrous magnesium sulphate was added and the mixture filtered. Evaporation of the ether left an oil which after triturating with benzene/light petroleum gave 1.31 g. of crystals, MP. 96- 97 C.

A'nalysis.-Found (percent): C, 81.6; H, 8.6; N, 4.5. C H NO requires (percent): C. 81.51; H, 8.8; N, 4.5.

This compound provides protection against metrazolinduced convulsions in mice. The ED (i.p.) is 60 mg./ kg. and the LD more than 400 mg./kg.

l 4 What is claimed is: 1. A compound having the formula:

in which A is a member of the group consisting of phenyl and benzyl, B is a member of the group consisting of phenyl, halophenyl, and methoxyphenyl, R is a member of the group consisting of hydrogen and methyl, X is a member of the group consisting of cyano, carboethoxy, hydroxymethyl, carboxamido, aminoethyl and the CO C H NMe radical and in which R and R are from the group consisting of benzyl and lower alkyl radicals.

2. A compound according to claim 1 which is 5-cyano- 5,5-diphenyl-1-diethylamin0-2-pentyne.

3. A compound according to claim 1 which is S-cyano- 5,5-diphenyl-1-benzylmethylamino-2-pentyne.

4. A compound according to claim 1 which is l-diethylamino-4-methyl-S-cyano-S,5-diphenyl-2-pentyne.

References Cited UNITED STATES PATENTS 9/1967 Vilke 260-570.8

ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant Examiner US. Cl. X.R. 

